1,1,3,3-tetramethylbutyl peroxyneodecanoate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

In the EOGRTS (OECD 443), oral (gavage) administration of 1,1,3,3 -tetramethylbutyl peroxyneodecanoate resulted in treatment-related effects on sperm motility and morphology in both F0 and F1 male rats at 450 mg/kg bw/day. Mean percentages of motile sperm and progressive sperm were markedly decreased. Motile and progressive sperm were absent in samples from a few males, and no progressive sperm was found in samples of some other males. In addition, mean numbers of cells with a detached head or with an abnormal neck had increased. In addition, a reduced fertility index was observed at 450 mg/kg bw/day. No such changes were seen at 50 or 150 mg/kg bw/day. A NOAEL of 150 mg/kg bw/day for sperm findings was also noted in an oral OECD 421 study with 10-wk pre-mating exposure of the males. Oral (gavage) administration at a dose level of 300 mg/kg bw/day for 90 days also resulted in findings in sperm concentration and motility and an associated increase in sperm abnormalities. After a 28-day observation period, these findings were not reversible in males treated at 300 mg/kg bw/day. The next lower level of 100 mg/kg bw/day was established as No Observed Adverse Effect Level (NOAEL) in males. Based on these studies with at least 90-day exposure of males, an overall NOAEL of 150 mg/kg bw/day was established for male reproductive toxicity.

In both the EOGRTS and OECD 421 study, female fertility was considered unaffected by treatment up to and including the high dose tested; the NOAEL for female reproductive toxicity therefore was at least 450 mg/kg bw/day.

The NOAEL for developmental toxicity in the EOGRTS was at least 450 mg/kg bw/day.

In the EOGRTS but not in the 90-day study, microscopic heart findings were noted in both male and female F0 and F1 rats with a NOAEL of ca. 50 mg/kg bw/day.

In all these studies of at least 90 day duration, dose-related kidney changes were noted in males which were considered related to alpha-2u-globulin nephropathy, a male-rat-specific syndrome with no relevance to man.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

150 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

K1 GLP study. NOAEL for females is at least 450 mg/kg/day.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

The oral administration of 1,1,3,3-tetramethylbutyl peroxyneodecanoate to pregnant rats by gavage during gestation days 5 -19, at dose levels of 0, 30, 175 or 1000 mg/kg bw/day resulted in a clear adverse effect on body weight gain and food consumption at the high dose level. Although some improvement was evident, cumulative body weight gains for females treated with 1000 mg/kg bw/day remained lower than controls throughout the dosing period with body weight gain adjusted for the contribution of gravid uterus also being markedly lower than controls. Taking into consideration the overall results, the NOAEL for the pregnant female rat was considered to be 175 mg/kg bw/day.

At 1000 mg/kg bw/day, fetal and litter weights were marginally lower than in controls with skeletal examination identifying a number of treatment-related variants. These observations were, however, considered to be due to maternal toxicity which resulted in slight reduction in fetal growth rather than an indication of a direct effect of the test item on fetal growth and development. The NOAEL for developmental toxicity was therefore considered to be 175 mg/kg/day, the limited findings noted at 1000 mg/kg bw/day were observed in the presence of clear maternal toxicity.

In the OECD 421 study the developmental NOAEL was established at 150 mg/kg bw/day based on a slightly lower mean body weight in pups of both sexes of the 450 mg/kg bw/day group compared to controls at PND13.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

175 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

GLP, Klimisch 1 study.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

 

Justification for classification or non-classification

In male rats, reduced sperm concentration and motility were observed associated with an increase in sperm morphological abnormalities. These findings were noted at 450 mg/kg bw/day in an EOGRTS (OECD 443) and in an OECD 421 study with 10-wk premating, and at 300 mg/kg bw/day in the 90-day study (OECD 408; see section 7.5). In addition, a reduced fertility index was observed in the EOGRTS at 450 mg/kg bw/day. Based on these results the substance is classified as toxic to reproduction category 1B (H360F). No classification is needed for developmental toxicity as the only findings noted were a lower fetal body weight and a number of skeletal variations which were seen in the presence of clear maternal toxicity at a high dose of 1000 mg/kg bw/day.